Identification and Structure-Activity Studies of 1,3-Dibenzyl-2-aryl imidazolidines as Novel Hsp90 Inhibitors.

Hsp90 (Heat shock protein 90) is involved in various processes in cancer occurrence and development, and therefore represents a promising drug target for cancer therapy. In this work, a virtual screening strategy was employed, leading to the identification of a series of compounds bearing a scaffold of 1,3-dibenzyl-2-aryl imidazolidine as novel Hsp90 inhibitors. Compound 4a showed the highest binding affinity to Hsp90α (IC50 = 12 nM) in fluorescence polarization (FP) competition assay and the strongest anti-proliferative activity against human breast adenocarcinoma cell line (MCF-7) and human lung epithelial cell line (A549) with IC50 values of 21.58 µM and 31.22 µM, respectively. Western blotting assays revealed that these novel Hsp90 inhibitors significantly down-regulated the expression level of Her2, a client protein of Hsp90, resulting in the cytotoxicity of these novel Hsp90 inhibitors. The molecular docking study showed that these novel Hsp90 inhibitors bound to the adenosine triphosphate (ATP) binding site at the N-terminus of Hsp90. Furthermore, structure-activity relationship studies indicated that the N-benzyl group is important for the anti-cancer activity of 1,3-dibenzyl-2-aryl imidazolidines.

Phospholipid transfer protein (PLTP) deficiency accelerates memory dysfunction through altering amyloid precursor protein (APP) processing in a mouse model of Alzheimer's disease.

Phospholipid transfer protein (PLTP) is a widely expressed lipid transfer protein participating in the transport of cholesterol and other lipids in the plasma and peripheral tissues. Recently, elevated amyloid ß (Aß) in young and aged PLTP-deficient brains had been reported. However, the role of PLTP in amyloid precursor protein (APP) processing and Alzheimer's disease (AD) pathology remains elusive. Here we first found that deficiency of PLTP accelerated memory dysfunction in APP/PS1ΔE9 AD model mice at the age of 3 months. Further characterization showed that PLTP deficiency increased soluble Aß peptides, and intracellular accumulation of Aß was illustrated, which might be due to disrupted APP turnover and the enhanced amyloidogenic pathway. Besides, reduced brain-derived neurotrophic factor (BDNF) was found in PLTP-deficient APP/PS1ΔE9 mice, and the BDNF level was negatively correlated with Aß42 content, instead of Aß40 content. In addition, autophagic dysfunction was found in the PLTP-deficient APP/PS1ΔE9 mice. Our data presented a novel model to link phospholipid metabolism to APP processing and also suggested that PLTP played an important role in Aß metabolism and would be useful to further elucidate functions of PLTP in AD susceptibility.

Rapid Isolation and Determination of Flavones in Biological Samples Using Zinc Complexation Coupled with High-Performance Liquid Chromatography.

Chlorophyll-type contaminants are commonly encountered in the isolation and determination of flavones of plant aerial plant parts. Heme is also a difficult background substance in whole blood analysis. Both chlorophyll and heme are porphyrin type compounds. In this study, a rapid method for isolating flavones with 5-hydroxyl or ortho-hydroxyl groups from biological samples was developed based on the different solubilities of porphyrin-metal and flavone-metal complexes. It is important that other background substances, e.g., proteins and lipids, are also removed from flavones without an additional processing. The recoveries of scutellarin, baicalin, baicalein, wogonoside and wogonin, which are the primary constituents of Scutellaria baicalensis (skullcaps) were 99.65% ± 1.02%, 98.98% ± 0.73%, 99.65% ± 0.03%, 97.59% ± 0.09% and 95.19% ± 0.47%, respectively. As a sample pretreatment procedure, this method was coupled to high-performance liquid chromatography (HPLC) with good separation, sensitivity and linearity and was applied to determine the flavone content in different aerial parts of S. baicalensis and in dried blood spot samples.

Hypoxia-inducible factor-1α mediates up-regulation of neprilysin by histone deacetylase-1 under hypoxia condition in neuroblastoma cells.

Hypoxia-inducible factor (HIF)-1 is the key transcriptional activator mediating both adaptive and pathological responses to hypoxia. The purpose of this study was to find the role of HIF-1 in regulating neprilysin (NEP) at the early stage of hypoxia and explore the underlying mechanism. In this study, we demonstrated that both NEP mRNA and protein levels in neuroblastoma cells were elevated in early stages of hypoxia. Over-expression of HIF-1α gene increased NEP mRNA/protein levels, as well as enzyme activity while knockdown of HIF-1α decreased them. Meanwhile, HIF-1α was shown to bind to histone deacetylase (HDAC)-1 and reduced the association of HDAC-1 with NEP promoter, thus activating NEP gene transcription in a de-repression way. In summary, our results indicated that hypoxia in the early stages would up-regulate NEP expression, in which interaction of HIF-1α and HDAC-1 may play a role. This study suggested that NEP up-regulation might be an adaptive response to hypoxia, which was mediated by HIF-1α binding to HDAC-1 at the early stage of hypoxia.

Blood-brain barrier dysfunction in mice induced by lipopolysaccharide is attenuated by dapsone.

Blood-brain barrier (BBB) dysfunction is a key event in the development of many central nervous system (CNS) diseases, such as septic encephalopathy and stroke. 4,4'-Diaminodiphenylsulfone (DDS, Dapsone) has displayed neuroprotective effect, but whether DDS has protective role on BBB integrity is not clear. This study was designed to examine the effect of DDS on lipopolysaccharide (LPS)-induced BBB disruption and oxidative stress in brain vessels. Using in vivo multiphoton imaging, we found that DDS administration significantly restored BBB integrity compromised by LPS. DDS also increased the expression of tight junction proteins occludin, zona occludens-1 (ZO-1) and claudin-5 in brain vessels. Level of reactive oxygen species (ROS) was reduced by DDS treatment, which may due to decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and NOX2 expression. Our results showed that LPS-induced BBB dysfunction could be attenuated by DDS, indicated that DDS has a therapeutic potential for treating CNS infection and other BBB related diseases.

Exploring the therapeutic potential of Sirt6-enriched adipose stem cell-derived exosomes in myocardial ischemia-reperfusion injury: unfolding new epigenetic frontiers.

BACKGROUND: The management of myocardial ischemia-reperfusion injury (MIRI) presents continuous therapeutic challenges. NAD-dependent deacetylase Sirtuin 6 (Sirt6) plays distinct roles in various disease contexts and is hence investigated for potential therapeutic applications for MIRI. This study aimed to examine the impact of Sirt6-overexpressing exosomes derived from adipose stem cells (S-ASC-Exo) on MIRI, focusing on their influence on AIM2-pyroptosis and mitophagy processes. The sirtuin family of proteins, particularly Sirtuin 6 (Sirt6), play a pivotal role in these processes. This study aimed to explore the potential therapeutic effects of Sirt6-enriched exosomes derived from adipose stem cells (S-ASC-Exo) on regulating MIRI. RESULTS: Bioinformatic analysis revealed a significant downregulation of Sirt6 in MIRI subjected to control group, causing a consequential increase in mitophagy and pyroptosis regulator expressions. Therefore, our study revealed that Sirt6-enriched exosomes influenced the progression of MIRI through the regulation of target proteins AIM2 and GSDMD, associated with pyroptosis, and p62 and Beclin-1, related to mitophagy. The introduction of S-ASC-Exo inhibited AIM2-pyroptosis while enhancing mitophagy. Consequently, this led to a significant reduction of GSDMD cleavage and pyroptosis in endothelial cells, catalyzing a deceleration in the progression of atherosclerosis. Extensive in vivo and in vitro assays were performed to validate the expressions of these specific genes and proteins, which affirmed the dynamic modulation by Sirt6-enriched exosomes. Furthermore, treatment with S-ASC-Exo drastically ameliorated cardiac functions and limited infarct size, underlining their cardioprotective attributes. CONCLUSIONS: Our study underscores the potential therapeutic role of Sirt6-enriched exosomes in managing MIRI. We demonstrated their profound cardioprotective effect, evident in the enhanced cardiac function and attenuated tissue damage, through the strategic modulation of AIM2-pyroptosis and mitophagy. Given the intricate interplay between Sirt6 and the aforementioned processes, a comprehensive understanding of these pathways is essential to fully exploit the therapeutic potential of Sirt6. Altogether, our findings indicate the promise of Sirt6-enriched exosomes as a novel therapeutic strategy in treating ischemia-reperfusion injuries and cardiovascular diseases at large. Future research needs to underscore optimizing the balance of mitophagy during myocardial ischemia to avoid potential loss of normal myocytes.

Design and analysis of self-priming extension DNA hairpin probe for miRNA detection based on a unified dynamic programming framework.

MicroRNAs (miRNAs) are potential biomarkers for cancer diagnosis and prognosis, methods for detecting miRNAs with high sensitivity, selectivity, and stability are urgently needed. Various nucleic acid probes that have traditionally been for this purpose suffer several drawbacks, including inefficient signal-to-noise ratios and intensities, high cost, and time-consuming method establishment. Computing tools used for investigating the thermodynamics of DNA hybridization reactions can accurately predict the secondary structure of DNA and the interactions between DNA molecules. Herein, NUPACK was used to design a series of nucleic acid probes and develop a phosphorothioated-terminal hairpin formation and self-priming extension (PS-THSP) signal amplification strategy, which enabled the ultrasensitive detection of miR-200a in serum samples. The free and binding energies of the DNA detection probes calculated using NUPACK, as well as the biological experimental results, were considered synthetically to select the best sequence and experimental conditions. A unified dynamic programming framework, NUPACK analysis and the experimental data, were complementary and improved the designed model in all respects. Our study demonstrates the feasibility of using computer technology such as NUPACK to simplify the experimental process and provide intuitive results.

In silico and in vitro analyses of a novel FoxO1 agonist reducing Aß levels via downregulation of BACE1.

AIMS: FoxO1 is an important target in the treatment of Alzheimer's disease (AD). However, FoxO1-specific agonists and their effects on AD have not yet been reported. This study aimed to identify small molecules that upregulate the activity of FoxO1 to attenuate the symptoms of AD. METHODS: FoxO1 agonists were identified by in silico screening and molecular dynamics simulation. Western blotting and reverse transcription-quantitative polymerase chain reaction assays were used to assess protein and gene expression levels of P21, BIM, and PPARγ downstream of FoxO1 in SH-SY5Y cells, respectively. Western blotting and enzyme-linked immunoassays were performed to explore the effect of FoxO1 agonists on APP metabolism. RESULTS: N-(3-methylisothiazol-5-yl)-2-(2-oxobenzo[d]oxazol-3(2H)-yl) acetamide (compound D) had the highest affinity for FoxO1. Compound D activated FoxO1 and regulated the expression of its downstream target genes, P21, BIM, and PPARγ. In SH-SY5Y cells treated with compound D, BACE1 expression levels were downregulated, and the levels of Aß1-40 and Aß1-42 were also reduced. CONCLUSIONS: We present a novel small-molecule FoxO1 agonist with good anti-AD effects. This study highlights a promising strategy for new drug discovery for AD.

Environmental effects of the establishment of pilot free trade zones: evidence from Chinese resource-based enterprises.

The establishment of pilot free trade zones (FTZs) is a key strategic measure taken by China to promote high-quality economic development, but there are still gaps in the research on how the establishment of FTZs affects the environmental performance of enterprises from a micro perspective. Using data from China's Shanghai and Shenzhen A-share resource-based listed enterprises from 2010 to 2020, this paper uses the difference-in-difference model to examine the impact of the establishment of FTZs on the environmental performance of enterprises. The study finds that after the city that the enterprise located is set up as a free trade zone (FTZ), enterprises' environmental performance has been significantly improved, and this effect has a continuous positive impact. As far as the influence mechanism is concerned, the main driving forces for the establishment of FTZs are technology effect, competition effect, and resource allocation effect, which are embodied in the significant improvement of enterprises' green technology innovation, total factor productivity, and environmental protection investment. The environmental performance of non-state-owned and large-scale resource-based enterprises is more prominently affected by the establishment of FTZs. In capital-intensive industries and the eastern region, the environmental performance improvement effect of the establishment of FTZs is more obvious. This study provides targeted suggestions for resource-based enterprises to effectively implement the environmental green development strategy.

Expression and significant roles of the lncRNA NEAT1/miR-493-5p/Rab27A axis in ulcerative colitis.

BACKGROUND: Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) have been reported to play regulatory roles in ulcerative colitis (UC). In this study, we aimed to determine the specific roles and action mechanism of the nuclear paraspeckle assembly transcript 1 (NEAT1) in UC. METHODS: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to determine the lncRNA NEAT1 and miR-493-5p expression levels in patients with UC and healthy volunteers. We determine the forecast linkage points of NEAT1 and miR-493-5p using Starbase and those of miR-493-5p and Rab27A using TargetScan, and further verified them using a double luciferase gene reporter kit. RT-qPCR and Western blot analysis were used to determine the lncRNA NEAT1, miR-493-5p, and Rab27A expression levels in lipopolysaccharide (LPS)-induced Caco-2 cells. Flow cytometry and cell counting kit-8 were used to assess Caco-2 cell viability. Tumor necrosis factor-α, interleukin (IL)-6, IL-8, and IL-1ß levels were determined via an enzyme-linked immunosorbent assay. RESULTS: Expression levels of NEAT1 were upregulated and those of miR-493-5p were downregualted in 10 ng/mL LPS-treated Caco-2 cells and patients with UC. Dual-luciferase gene reporter assay revealed that miR-493-5p is linked to NEAT1, and Rab27A is a downstream target of miR-493-5p. Overexpression of miR-493-5p inhibited the apoptosis and inflammation in LPS-treated Caco-2 cells. Moreover, downregulation of lncRNA NEAT1 expression also inhibited the apoptosis and inflammation in LPS-treated Caco-2 cells, which was reversed by Rab27A plasmid cotransfection. CONCLUSION: Our results revealed that NEAT1 participates in UC progression by inhibiting miR-493-5p expression.

Chemokines in patients with Alzheimer's disease: A meta-analysis.

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease in elderly people. Many researches have reported that neuroinflammation is related to AD. Chemokines are a class of small cytokines that play important roles in cell migration and cell communication, which involved in neuroinflammation. Up to now there is no meta-analysis to explore the difference of chemokines between AD patients and healthy elderly individuals. Method: We searched PubMed, Web of science, Cochrane library, EMBASE and Scopus databases from inception to January 2022. Data were extracted by two independent reviewers, and the Review Manager 5.3 was used for the meta-analysis. Result: Thirty-two articles were included and analyzed. The total number of participants in the included study was 3,331. We found that the levels of CCL5 (SMD = 2.56, 95% CI: 1.91-3.21), CCL15 (SMD = 3.30, 95% CI: 1.48-5.13) and IP-10 (SMD = 3.88, 95% CI: 1.84-5.91) in the plasma of AD patients were higher than healthy people. MCP-1 protein (SMD = 0.67, 95% CI: 0.29-1.05) in the AD patients' CSF was higher than healthy controls. Conclusion: These results suggested that chemokines may play an important role in AD. These findings could provide evidences for the diagnosis and treatment of AD. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021278736, identifier: CRD42021278736.

Selenite Ameliorates Cadmium-induced Cytotoxicity Through Downregulation of ROS Levels and Upregulation of Selenoprotein Thioredoxin Reductase 1 in SH-SY5Y Cells.

Cadmium (Cd) as a ubiquitous toxic heavy metal in the environment, causes severe hazards to human health, such as cellular stress and organ injury. Selenium (Se) was reported to reduce Cd toxicity and the mechanisms have been intensively studied so far. However, it is not yet crystal clear whether the protective effect of Se against Cd-induced cytotoxicity is related to selenoproteins in nerve cells or not. In this study, we found that Cd inhibited selenoprotein thioredoxin reductase 1 (TrxR1; TXNRD1) and decreased the expression level of TrxR1, resulting in cellular oxidative stress, and Se supplements ameliorated Cd-induced cytotoxicity in SH-SY5Y cells. Mechanistically, the detoxification of Se against Cd is attributed to the increase of the cellular TrxR activity and upregulated TrxR1 protein level, culminating in strengthened antioxidant capacity. Results showed that Se supplements attenuated the ROS production and apoptosis in SH-SY5Y cells, and significantly mitigated Cd-induced SH-SY5Y cell death. This study may be a valuable reference for shedding light on the mechanism of Cd-induced cytotoxicity and the role of TrxR1 in Se-mitigated cytotoxicity of Cd in neuroblast cells, which may be helpful for understanding the therapeutic potential of Cd and Se in treating or preventing neurodegenerative diseases, like Alzheimer's disease (AD) and Parkinson's disease (PD).

Efficacy and Safety of Five Broad-Spectrum Antiseizure Medications for Adjunctive Treatment of Refractory Epilepsy: A Systematic Review and Network Meta-analysis.

BACKGROUND: Overall, up to one-third of epilepsy patients have drug-resistant epilepsy. However, there was previously no meta-analysis to support the guidelines for broad-spectrum antiseizure medication selection for the adjunctive treatment of refractory epilepsy. In the present meta-analysis, we assessed the efficacy and safety of three second-generation broad-spectrum antiseizure medications, lamotrigine (LTG), levetiracetam (LEV), and topiramate (TPM), and two third-generation broad-spectrum antiseizure medications, perampanel (PER) and lacosamide (LCM), for the adjunctive treatment of refractory epilepsy. METHODS: We systematically searched PubMed, Embase, and CENTRAL from inception to July 15, 2022. The studies included in the meta-analysis were required to meet the following criteria: (1) be randomized, double-blind clinical trials; (2) include patients aged >2 years with a clinical diagnosis of drug-resistant epilepsy; (3) have at least 8 weeks for the treatment period excluding the titration phase; and (4) report the outcomes of seizure response, seizure freedom and the withdrawal rate due to treatment-emergent adverse effects. Data were extracted, and the risk of bias for each study was assessed by two authors independently using RoB2 tools. We performed the network meta-analysis for each outcome through a group of programs in the mvmeta and network packages in Stata. Relative odds ratios with 95% confidence intervals were calculated as the result of the analyses. The surface under the cumulative ranking curve (SUCRA) and mean ranks were used to rank these treatments. RESULTS: Forty-two randomized controlled trials (RCTs) (LTG-placebo: n = 6, LEV-placebo: n = 13, TPM-placebo: n = 9, PER-placebo: n = 6, LCM-placebo: n = 7, LEV-TPM: n = 1) with 10257 participants (LTG = 569, LEV = 1626, TPM = 701, PER = 1734, LCM = 1908, placebo = 3719) were included. Levetiracetam had subequal efficacy in 50 % seizure frequency reduction to TPM [odds ratio (OR) 1.00, 95% confidence interval (CI) 0.73-1.38], and LEV had a higher rate of ≥ 50% seizure frequency reduction than LCM (OR 1.49, 95% CI 1.11-2.01) and PER (OR 1.68, 95% CI 1.24-2.29). Levetiracetam was also related to a higher proportion of seizure freedom participants than TPM (OR 1.87, 95% CI 1.20-2.89), PER (OR 2.23, 95% CI 1.12-4.43), and LCM (OR 2.97, 95% CI 1.46-6.05). In addition, LEV was associated with a lower risk of experiencing at least one treatment-emergent adverse event (TEAE) than PER (OR 0.63, 95% CI 0.46-0.85) and TPM (OR 0.51, 95 % CI 0.36-0.72) and a lower proportion of patients experiencing TEAEs leading to discontinuation than PER (OR 0.51, 95% CI 0.27-0.97) and TPM (OR 0.50, 95 % CI 0.27-0.93). CONCLUSIONS: Third-generation drugs (PER and LCM) had no advantages in terms of efficacy and safety for adjunctive treatment of refractory epilepsy compared with several second-generation drugs (LEV and LTG). Levetiracetam was the priority choice for adjunctive treatment of refractory epilepsy. Perampanel and LCM had no advantages in terms of efficacy and safety among the five drugs. REGISTRATION: PROSPERO registration number, CRD42022344153; last edited on December 23, 2022.

The Effect of N6-Methyladenosine Regulators and m6A Reader YTHDC1-Mediated N6-Methyladenosine Modification Is Involved in Oxidative Stress in Human Aortic Dissection.

Aortic dissection (AD) develops pathological changes in the separation of the true and false aortic lumen, with high lethality. m6A methylation and oxidative stress have also been shown to be involved in the onset of AD. Through bioinformatics methods, three differentially expressed m6A regulators (YTHDC1, YTHDC2, and RBM15) were excavated from the GSE52093 dataset in the Gene Expression Omnibus (GEO) database, and functional enrichment analysis of the differentially expressed genes (DEGs) regulated by m6A regulators was performed. Then, the genes with oxidative stress-related functions among these genes were found. The protein interaction network of the oxidative stress-related genes and the competing endogenous RNA- (ceRNA-) miRNA-mRNA network were constructed. Among them, DHCR24, P4HB, and PDGFRA, which have m6A differences in AD samples, were selected as key genes. We also performed immune infiltration analysis, as well as cell-gene correlation analysis, on samples from the dataset. The results showed that YTHDC1 was positively correlated with macrophage M1 and negatively correlated with macrophage M2. Finally, we extracted AD and healthy aorta RNA and protein from human tissues that were taken from AD patients and patients who received heart transplants, performed quantitative real-time PCR (qRT-PCR) on YTHDC2 and RBM15, and performed qRT-PCR and western blot (WB) detection on YTHDC1 to verify their differences in AD. The mRNA and protein levels of YTHDC1 were consistent with the results of bioinformatics analysis and were downregulated in AD. Immunofluorescence (IF) was used to colocalize YTHDC1 and endothelial cell marker CD31. After knocking down YTHDC1 in human umbilical vein endothelial cells (HUVECs), reactive oxygen species (ROS) levels had a tendency to increase and the expression of peroxide dismutase SOD2 was decreased. This study provides assistance in discovering the role of m6A regulator YTHDC1 in AD. In particular, m6A modification participates in oxidative stress and jointly affects AD.

Molecular docking and molecular dynamics simulations studies on the protective and pathogenic roles of the amyloid-ß peptide between herpesvirus infection and Alzheimer's disease.

The protective innate immune response of ß-amyloid peptide (Aß) has been indicated as a risk factor for Alzheimer's disease (AD) due to the rapid amyloidosis. In order to obtain molecular-level insights into the protective and pathogenic roles of Aß, the binding modes between Aß1-42 and the envelop glycoprotein D (gD) of Herpes simplex virus-1 (HSV-1)/Aß1-42 were theoretically investigated by using molecular docking, molecular dynamics (MD) simulations and binding free energy decomposition methods in the present study. The Aß1-42 stably binds to the envelop gD via intermolecular hydrogen bonds and van der Waals (vdW) interactions. The Aß1-42 acquires its equilibrium with higher fluctuation amplitude and a better structured C-terminal in the HSV-1 gD-Aß1-42 complex comparing to that in the Aß1-42-Aß1-42 complex. The amino acid residues of Aß1-42 involved in the formation of the Aß1-42 dimer are fully free and accessible in the HSV-1 gD-Aß1-42 complex. It is favorable for the Aß1-42 monomer to interact with the HSV-1 gD-Aß1-42 complex. It may be responsible for the rapid amyloidosis which entraps the herpesvirus as well as causing AD.

Proteomics analysis of lipid droplets in mouse neuroblastoma cells.

Lipid droplets (LDs) are intracellular droplets containing phospholipids and neutral lipids. It is well known that LDs are organelles with a rich proteome. In the nervous system, these droplets may play an important role in maintaining the normal physiological function of nerve cells. Moreover, LDs may relate to the neurodegenerative disorders, such as Alzheimer's disease (AD). However, more information is still needed about the function of LDs. In the study presented here, we identified the protein composition of mouse neuroblastoma (N2a) cell LDs using immunodetection and high-performance liquid chromatography (HPLC) coupled with mass spectrometry (MS). Seventy three LDs proteins were identified. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to investigate the potential functions of these proteins. Subsequently, the relationships among the proteins were analyzed by constructing a protein-protein interaction (PPI) network. N2a cell LDs contain multiple Rab GTPases, chaperones, and proteins involved in ubiquitination and transport. Some of these proteins were known to modulate LD formation and were related to the function of nerve cells. This work presents the proteome of N2a cell LDs and will help to identify the role of LDs in the nervous system.

Significant role of long non-coding RNA MALAT1 in deep vein thrombosis via the regulation of vascular endothelial cell physiology through the microRNA-383-5p/BCL2L11 axis.

Deep vein thrombosis (DVT) is a vascular disease. The long non-coding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), is positively expressed in DVT tissues, and regulates the biological behavior of endothelial progenitor cells. Here, we explored whether MALAT1 affected the physiology of human vascular endothelial cells (HUVECs) and analyzed its underlying mechanism. To overexpress/silence the expression of MALAT1 in HUVECs, MALAT1-plasmid/MALAT1-small interfering RNA (siRNA) was used. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and flow cytometry analyses were performed to observe the cell viability and apoptosis. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to determine the apoptosis-related protein and gene expression levels. We used Starbase software to predict the associations among MALAT1, microRNA (miR)-383-5p, and BCL2-like 11 (BCL2L11). Luciferase reporter assay was used to validate their relationship. Compared to the control vector group, MALAT1-plasmid suppressed the viability and induced apoptosis of HUVECs, while improving Bcl-2-associated X protein (Bax) expression and decreasing Bcl-2 expression. There was an interaction between MALAT1 and miR-383-5p. Compared to the control siRNA group, MALAT1-siRNA increased the cell viability, reduced cell apoptosis, upregulated Bcl-2 expression, and suppressed Bax expression. These changes were reversed by the miR-383-5p inhibitor. Additionally, we verified that BCL2L11 is a target of miR-383-5p. miR-383-5p improved the cell proliferation, while decreasing cell apoptosis in HUVECs by targeting BCL2L11. Therefore, the lncRNA-MALAT1/miR-383-5p/BCL2L11 axis may be effective for DVT treatment.

Compared of efficacy and safety of high-dose donepezil vs standard-dose donepezil among elderly patients with Alzheimer's disease: a systematic review and meta-analysis.

BACKGROUND: Donepezil is a first-line drug for the treatment of Alzheimer's disease (AD). However, there are no meta-analyses on efficacy and safety of high-dose versus standard-dose donepezil in the treatment of moderate-to-severe AD. RESEARCH DESIGN AND METHODS: We searched for randomized controlled trials (RCTs) from 1993 to May 2021 PubMed, Cochrane Library, EMBASE, Web of Science, and Scopus databases. The outcomes of the meta-analysis included cognitive function, global assessment, and the incidence of adverse events and serious adverse events. RESULTS: Five RCTs (2974 people) were included in this meta-analysis. The improvement of cognitive function was significant among the patients with the treatment of high-dose donepezil [SMD = 0.12, 95% CI: 0.03 ~ 0.22; p = 0.01]. Between the two groups, there was no significant difference in global assessment. Compared with standard-dose donepezil, there was no difference in the incidence of adverse events when high-dose donepezil was used. However, it was found that high-dose donepezil administration increased the risk of heart problems through subgroup analysis of the two serious adverse events. CONCLUSION: High-dose donepezil is more effective than standard-dose donepezil in improving cognitive function of the elderly with moderate-to-severe AD. However, more attention should be paid to patients with heart problems when high-dose donepezil was used.

Transition-metal-catalyzed remote C-H functionalization of thioethers.

In the last decade, transition-metal-catalyzed direct C-H bond functionalization has been recognized as one of most efficient approaches for the derivatization of thioethers. Within this category, both mono- and bidentate-directing group strategies achieved the remote C(sp2)-H and C(sp3)-H functionalization of thioethers, respectively. This review systematically introduces the major advances and their mechanisms in the field of transition-metal-catalyzed remote C-H functionalization of thioethers from 2010 to 2021.

Relationship between serum homocysteine, fibrinogen, lipoprotein-a level, and peripheral arterial disease: a dose-response meta-analysis.

AIM: At present, the relationship between serum homocysteine (Hcy), fibrinogen (FIB), lipoprotein-a (LPa), and PAD is uncertain, and there has been no meta-analysis to establish the dose-response relationship between their exposure levels and PAD. METHODS AND RESULTS: Relevant literature published in PubMed, Embase, and Web of Science was retrieved. The robust error meta-regression method was used to assess the linear and non-linear dose-response relationship between exposure level and PAD risk. A total of 68 articles, involving 565,209 participants, were included. Combined with continuous variables, the serum Hcy, FIB, and LPa levels of PAD patients were significantly higher than those of healthy individuals. The odds ratios (ORs) of PAD for individuals with high Hcy, FIB, and LPa levels compared with those with low levels were 1.47, 1.14, and 1.76, respectively. The study also showed that circulating Hcy, FIB, and LPa were significantly elevated in patients with PAD compared with controls. The level of Hcy and the risk of PAD presented a U-shaped distribution. The nonlinear dose-response model showed that each 1 µmol/L increase in serum Hcy increased the risk of PAD by 7%. Similarly, for each 10 mg/dL FIB and 10 mg/dL LPa increases, the risk of PAD increased by 3% and 6%, respectively. CONCLUSIONS: This meta-analysis provided evidence that elevated Hcy, PIB, and LPa levels may increase the risk of PAD, and the risk of PAD increases with the increase in serum exposure within a certain range. By controlling Hcy level, the incidence of PAD may be reduced to control the PAD growing epidemic. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42021250501), https://www.crd.york.ac.uk/prospero/.